Method for producing indole compound

ABSTRACT

The present invention aims to provide a new method for producing an indole compound or a salt thereof, which has an ITK inhibitory action, and is useful for the prophylaxis or treatment of inflammatory disease. 
     The present invention is a method for producing N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide, which comprises a step of reacting

TECHNICAL FIELD

The present invention relates to a new method for producing an indolecompound or a salt thereof, which is useful as an inducible T cellkinase (ITK) inhibitor, and an intermediate thereof.

BACKGROUND ART

Patent Document 1 discloses a compound useful as an ITK inhibitor, and amethod for producing the same.

DOCUMENT LIST Patent Document

-   Patent Document 1: WO 2011/065402

SUMMARY OF THE INVENTION

The present invention aims to provide a new method for producing anindole compound or a salt thereof, which is useful for the prophylaxisor treatment of inflammatory disease, and the like.

Embodiments of the present invention are shown in the following (1) to(16).

(1) A method of producingN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide(formula [I]

which comprises a step of removing the protecting group fromN-[2-(6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide(formula [III]

to give a compound of the formula [I].(2) A method of producingN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamidemonohydrochloride (formula [II]

which comprises a step of reactingN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide(formula [I]

with hydrogen chloride to give a compound of the formula [II].(3) A method of producingN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamidemonohydrochloride (formula [II]

which comprises a step of removing the protecting group fromN-[2-(6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide(formula [III]

to giveN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide(formula [I]

anda step of treating a compound of the formula [I] with hydrogen chlorideto give a compound of the formula [II].(4) The method of (1) or (3), which further comprises a step of reactingN-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine(formula [V]

with (2S)-2-(morpholin-4-yl)propanoic acid (formula [IV]

or reactive derivative thereof or a salt thereof to giveN-[2-(6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide(formula [III]

(5) The method of (4), which further comprises a step of subjecting acompound of the formula [VI]

wherein R¹ and R² are each independently hydrogen, C₁₋₆ alkyl or C₁₋₆alkoxy,to a reduction reaction to giveN-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine(formula [V]

(6) The method of (5), which further comprises a step of reacting acompound of the formula [VII]

wherein R² is as defined above,with a compound of the formula [XI]

wherein R² is as defined above,to give a compound of the formula [VI]

wherein R¹ and R² are as defined above.(7) The method of (6), which further comprises a step of subjecting acompound of the formula [VIII]

wherein R¹ is as defined above,to tetrahydropyranylation to give a compound of the formula [VII]

wherein R¹ is as defined above.(8) The method of (7), which further comprises a step of reacting6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (formula[IX]

with a compound of the formula [X]

whereinM is sodium or potassium, andR¹ is as defined above,to give a compound of the formula [VIII]

wherein R² is as defined above.(9) The method of (2) or (3), which further comprises a step ofpurifyingN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamidemonohydrochloride (formula [II]

with 1-propanol.(10) A method of producing a compound of the formula [XI]

wherein R² is as defined above,which comprises a step of subjecting a compound of the formula [XII]

wherein R² is as defined above,to methylation.(11)N-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine(formula [V])

(12)N-[2-(6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide(formula [III])

(13) A compound of the formula [VI]

wherein R¹ and R² are as defined above.(14) A compound of the formula [VII]

wherein R¹ is as defined above.(15) A compound of the formula [VIII]

wherein R¹ is as defined above.(16) A compound of the formula [XI]

wherein R² is as defined above.

Effect of the Invention

According to the production method of the present invention, an indolecompound having an ITK inhibitory action, which is useful for theprophylaxis or treatment of inflammatory disease, and the like, can beproduced via compound considered to be free from safety concerns, in afew steps and in good yield. In addition, a new intermediate forproducing the indole compound can also be provided by the method.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows multi record of powder X-ray diffraction pattern ofN-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine.The axis of ordinate shows diffraction strength (cps: counts persecond), and the axis of abscissas shows diffraction angle 2θ°.

EMBODIMENTS OF THE INVENTION

The definitions of the terms used in the present specification are asfollows.

The “C₁₋₆ alkyl” means straight chain or branched chain alkyl having 1to 6 carbon atoms, preferably straight chain or branched chain alkylhaving 1 to 4 carbon atoms. Examples thereof include methyl, ethyl,propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl,isopentyl, tert-pentyl, 1-ethylpropyl, neo-pentyl, hexyl, 2-ethylbutyl,3,3-dimethylbutyl and the like. Methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl and tert-butyl are preferable, and methyl isparticularly preferable.

The “C₁₋₆ alkoxy” means alkyl-oxy wherein the alkyl moiety is theabove-defined “C₁₋₆ alkyl”. Examples thereof include methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy, tert-butoxy,pentoxy, isopentoxy, tert-pentoxy, 1-ethylpropoxy, neopentoxy, hexoxy,2-ethylbutoxy, 3,3-dimethylbutoxy and the like. Methoxy, ethoxy,propoxy, isopropoxy, butoxy, isobutoxy, sec-butoxy and tert-butoxy arepreferable, and methoxy is particularly preferable.

Compounds [III], [V], [VI] and [VII] of the present invention havetetrahydropyranyl as a protecting group at the 1-position on the4,5,6,7-tetrahydro-1H-indazole moiety. The compounds may havemethoxymethyl instead of tetrahydropyranyl.

The protecting group at the 1-position on the4,5,6,7-tetrahydro-1H-indazole moiety in the compound of the presentinvention is preferably tetrahydropyranyl.

The “reactive derivative” of the carboxylic acid may be any carboxylicacid derivative as long as it can form an amide bond. Examples thereofinclude acid halides, anhydrides and the like. Acid halides arepreferable.

The “salt” of the compound may be any salt as long as it forms a saltwith the compound of the present invention. Examples thereof includesalts with inorganic acid, salts with organic acid, salts with inorganicbase, salts with organic base, salts with amino acid, and the like.

Examples of the salts with inorganic acid include salts withhydrochloric acid, nitric acid, sulfuric acid, phosphoric acid,hydrobromic acid and the like.

Examples of the salts with organic acid include salts with oxalic acid,maleic acid, citric acid, fumaric acid, lactic acid, malic acid,succinic acid, tartaric acid, acetic acid, trifluoroacetic acid,gluconic acid, ascorbic acid, methanesulfonic acid, benzenesulfonicacid, p-toluenesulfonic acid and the like.

Examples of the salts with inorganic base include sodium salt, potassiumsalt, calcium salt, magnesium salt, ammonium salt and the like.

Examples of the salts with organic base include salts with methylamine,diethylamine, trimethylamine, triethylamine, ethanolamine,diethanolamine, triethanolamine, ethylenediamine,tris(hydroxymethyl)methylamine, dicyclohexylamine,N,N′-dibenzylethylenediamine, guanidine, pyridine, picoline, choline,cinchonine, meglumine and the like.

Examples of the salts with amino acid include salts with lysine,arginine, aspartic acid, glutamic acid and the like.

The salt of compound [IV] is preferably hydrochloride, particularlypreferably monohydrochloride.

The “halogen” means fluorine, chlorine, bromine, iodine or the like.Chlorine and bromine are preferable, and chlorine is particularlypreferable.

The “methylating agent” means a reagent capable of introducing methylinto a reactive functional group such as —NH— and the like. Examplesthereof include methyl iodide, dimethylsulfuric acid and the like.Methyl iodide is preferable.

The formula [VI]

wherein R¹ and R² are each independently hydrogen, C₁₋₆ alkyl or C₁₋₆alkoxy,is preferably the formula [VI-1] (benzyl2-[4-(N-benzyloxycarbonyl-N-methylamino)-2-nitrophenyl]-3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate)

The formula [VII]

wherein R¹ is as defined above,

is preferably formula [VII-1] (benzyl3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate)

The formula [VIII]

wherein R¹ is as defined above,is preferably formula [VIII-1] (benzyl3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-oxopropanoate)

The formula [X]

wherein M is sodium or potassium, R² is as defined above,is preferably formula [X-1] (monobenzyl potassium malonate)

The moiety

in the above-mentioned compounds [VI], [VII], [VIII] and [X], and themoiety

in the above-mentioned compounds [VI], [XI] and [XII] and thebelow-mentioned compound [XIV] are carboxy-protecting groups, preferablybenzyl (R² is hydrogen). The moieties can be each replaced by anothermoiety. Examples of such moiety include 4-methoxybenzyl (R² is methoxy)and 4-methylbenzyl (R² is methyl).

The compound of the present invention may exist as a tautomer. In thiscase, the compound of the present invention may exist as a singletautomer or a mixture thereof.

The compound of the present invention may contain one or more asymmetriccarbons. In this case, the compound of the present invention may existas a single enantiomer, a single diastereomer, a mixture of enantiomersor a mixture of diastereomers.

The compound of the present invention may exist as an atropisomer. Inthis case, the compound of the present invention may exist as a singleatropisomer or a mixture thereof.

The compound of the present invention may simultaneously contain pluralstructural characteristics that produce the above-mentioned isomers.Moreover, the compound of the present invention may contain theabove-mentioned isomers at any ratio.

Unless otherwise referred to note, the formulae, chemical structures andcompound names indicated in the present specification without specifyingthe stereochemistry thereof encompass all the above-mentioned isomersthat may exist.

A diastereomeric mixture can be separated into each diastereomer by aconventional method such as chromatography, crystallization and thelike. In addition, each diastereomer can also be produced by using astereochemically single starting material, or by a synthetic methodemploying a stereoselective reaction.

An enantiomeric mixture can be separated into each single enantiomer bya method well known in the art.

For example, a diastereomic mixture can be prepared by reacting anenantiomeric mixture with a substantially pure enantiomer that is knownas a chiral auxiliary, and the diastereomeric mixture can be separatedinto single diastereomer having a high isomer ratio or substantiallypure single diastereomer by a standard method such as fractionalcrystallization and chromatography. The separated diastereomer can beconverted to a desired enantiomer by removing the added chiral auxiliaryby cleavage.

In addition, an enantiomeric mixture can also be directly separated by achromatography method using a chiral solid phase well known in the art.

Alternatively, one of enantiomers can also be obtained by using asubstantially pure optically active starting material or by employingstereoselective synthesis (asymmetric induction) of a prochiralintermediate using a chiral auxiliary and an asymmetric catalyst.

The absolute steric configuration can be determined based on the X-raycrystal analysis of the crystalline product or intermediate. In thiscase, a crystalline product or intermediate derivatized with a reagenthaving an asymmetric center with a known steric configuration may beused if necessary.

The production method of the present invention is concretely explainedin the following.

In each step, the treatment after reaction can be performed by a generalmethod, and the product can be purified by appropriately selecting orcombining a conventional method such as distillation, crystallization,recrystallization, column chromatography, preparative HPLC, slurrywashing and the like. The product may be directly used in the next stepwithout isolation or purification.

Step 1

wherein R² is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkoxy, and Hal is halogen.

Compound [XII] can be obtained by reacting 4-fluoro-3-nitroaniline(compound [XIII]) with compound [XIV] in an ester solvent (ethylacetate, etc.), an ether solvent (tetrahydrofuran, dimethyl ether,diethyl ether, etc.), a polar solvent (dimethyl sulfoxide,N,N-dimethylformamide, etc.) or the like or in a mixed solvent thereof,in the presence of an inorganic base (sodium hydrogencarbonate,potassium hydrogencarbonate, sodium carbonate, potassium carbonate) oran organic base (triethylamine, N,N-diisopropylethylamine, pyridine,etc.). When an inorganic base is used, water may be mixed with aninorganic base. The amount of compound [XIV] is 1.05 equivalent to 1.5equivalent, preferably 1.1 equivalent, relative to4-fluoro-3-nitroaniline. The amount of the base is 1.5 equivalent to 1.1equivalent, preferably 1.3 equivalent, relative to4-fluoro-3-nitroaniline. The reaction temperature is 0° C. to 50° C.,preferably room temperature. The reaction time is 1 hr to 10 hr,preferably 2 hr to 4 hr, particularly preferably 3 hr.

Compound [XIV] may be a commercially available product, or can beprepared by a known method from a benzyl alcohol having a desiredsubstituent and a carbonyldihalogen such as phosgene and the like.

Step 2

wherein R² is as defined above.

Compound [XI] can be obtained by reacting compound [XII] with amethylating agent such as methyl iodide, dimethylsulfuric acid and thelike, in a solvent such as a polar solvent (dimethyl sulfoxide,N,N-dimethylformamide, N,N-dimethylacetamide, etc.), an ether solvent(tetrahydrofuran, dimethyl ether, diethyl ether, etc.) and the like, inthe presence of an inorganic base (cesium carbonate, sodium carbonate,potassium carbonate, sodium hydrogencarbonate, potassiumhydrogencarbonate, sodium hydride, sodium tert-butoxide, etc.). Theamount of the methylating agent is 1.1 equivalent to 1.5 equivalent,preferably 1.2 equivalent, relative to compound [XII]. The amount of theinorganic base is 1.1 equivalent to 1.5 equivalent, preferably 1.2equivalent, relative to compound [XII]. The reaction temperature is 0°C. to 40° C., preferably 20° C. to 10° C. The reaction time is 1 hr to10 hr, preferably 2 hr to 4 hr, particularly preferably 3 hr.

Step 3

wherein R¹ is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkoxy, and M is sodium orpotassium.(1) 6,6-Dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid(compound [IX]) is reacted with a condensing agent such as1,1′-carbonyldiimidazole, 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide,dicyclohexylcarbodiimide and the like, in a polar solvent (dimethylsulfoxide, N,N-dimethylformamide, etc.), an aromatic hydrocarbon(benzene, toluene, etc.), an ether solvent (tetrahydrofuran, dimethylether, diethyl ether, etc.) or the like or in a mixed solvent thereof,for 1 hr to 3 hr, preferably for 2 hr or more.(2) Separately, compound [X] is reacted with magnesium chloride in apolar solvent (dimethyl sulfoxide, N,N-dimethylformamide, etc.), anaromatic hydrocarbon (benzene, toluene, etc.), an ether solvent(tetrahydrofuran, dimethyl ether, diethyl ether, etc.) or the like or ina mixed solvent thereof, and the resulting product is mixed with themixture obtained in (1), and the mixture is reacted for 1 hr to 3 hr,preferably for 3 hr, to give compound [VIII]. In this reaction, thereaction rate can be increased and the yield can be improved, byaddition of a tertiary amine (triethylamine, diisopropylethylamine,etc.). To improve the yield, the amount of compound [X] is 1.5equivalent or more, preferably 2 equivalent, relative to compound [IX].The amount of the condensing agent is 1.0 equivalent to 1.5 equivalent,preferably 1.1 equivalent, relative to compound [IX]. The amount of themagnesium chloride is 1.1 equivalent to 1.5 equivalent, preferably 1.25equivalent, relative to compound [X]. When a tertiary amine is added,solvent amount thereof may be added 2 hr after reaction initiation, orlater. The reaction temperature is 0° C. to 100° C., preferably 45° C.to 55° C. The reaction mixture is preferably warmed to 65° C. to 75° C.depending on the reaction progress. The reaction time is 1 hr to 10 hr,preferably 2 hr to 6 hr.

Compound [X] may be a commercially available product, or can be preparedby a known method from a benzyl alcohol having a desired substituent andmalonic acid.

Step 4

wherein R¹ is as defined above.

Compound [VII] can be obtained by reacting compound [VIII] with3,4-dihydro-2H-pyran in a solvent such as an ester solvent (ethylacetate, etc.), a polar solvent (N,N-dimethylformamide, etc.), an ethersolvent (tetrahydrofuran, etc.), an aromatic hydrocarbon (toluene, etc.)and the like, in the presence of an organic acid (p-toluenesulfonicacid, methanesulfonic acid, etc.). The amount of the3,4-dihydro-2H-pyran is 1.1 equivalent to 2 equivalent, preferably 1.5equivalent, relative to compound [VIII]. The amount of the organic acidis a catalyst amount (for example 0.05 equivalent). The reactiontemperature is 0° C. to 50° C., preferably 15° C. to 30° C. The reactiontemperature is 1 hr to 5 hr, preferably 2 hr. The solvent to be used forthis reaction is preferably ethyl acetate, since the production ofimpurities can be suppressed, compared with N,N-dimethylformamide,tetrahydrofuran or toluene.

While the configuration of the carbon at the 2-position on thetetrahydropyranyl in compound [VII] may contain R and S, compound [VII]can be used in the next step without optical resolution.

Step 5

wherein R¹ and R² are as defined above.

Compound [VI] can be obtained by reacting compound [VII] with compound[XI] in an ether solvent (tetrahydrofuran, dimethyl ether, diethylether, etc.), a polar solvent (dimethyl sulfoxide,N,N-dimethylformamide, N,N-dimethylacetamide, etc.) or a mixed solventthereof, in the presence of an inorganic base (tripotassium phosphate,cesium carbonate, sodium carbonate, potassium carbonate, etc.). Themolar ratio of compound [VII] and compound [XI] is preferably about 1:1.The amount of the inorganic base is 2 equivalent to 3 equivalent,preferably 2.5 equivalent, relative to compound [VII]. The reactiontemperature is 30° C. to 100° C., preferably 50° C. to 60° C. Thereaction time is 2 hr to 30 hr, preferably 20 hr.

Step 6

wherein R¹ and R² are as defined above.

N-[2-[6,6-Dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine(compound [V]) can be obtained by subjecting compound [VI] to areduction reaction by hydrogenation in an alcohol (methanol, ethanol,1-propanol, 2-propanol, etc.) alone, or in a mixed solvent of an alcoholwith an aromatic hydrocarbon (toluene, benzene, etc.), an ether solvent(tetrahydrofuran, dimethyl ether, diethyl ether, etc.), an ester solvent(ethyl acetate, etc.) or the like, in the presence of a palladiumcatalyst (palladium on carbon (preferably PE type), palladium black,palladium hydroxide carbon or the like, preferably palladium on carbonPE type). The hydrogen pressure is 1 atm to 10 atm, preferably 3 atm to4 atm. The reaction temperature is 0° C. to 50° C., preferably 15° C. to30° C. The reaction time is 5 hr to 40 hr, preferably 20 hr.

Since compound [V] is crystallized, it can be purified. In particular,the color substance produced in the reaction can be removed. Whenpurification is performed by recrystallization or slurry washing, amixed solvent of toluene and 2-propanol is preferably used.

Step 7

N-[2-(6,6-Dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide(compound [III]) can be obtained by reacting compound [V] with(S)-2-(morpholin-4-yl)propanoic acid (compound [IV]) or a salt thereof,using a condensing agent (1-ethyl-3-(3-dimethylaminopropyl)carbodiimideor a salt thereof, dicyclohexylcarbodiimide, diisopropylcarbodiimide,etc.), in the presence of a reaction accelerator (1-hydroxybenzotriazoleor a hydrate thereof, etc.), in a solvent such as polar solvent(dimethyl sulfoxide, N,N-dimethylformamide, etc.), an ether solvent(tetrahydrofuran, dimethyl ether, diethyl ether, etc.) and the like.When a salt of compound [IV] is used, a base (sodium hydrogencarbonate,potassium hydrogencarbonate, sodium carbonate, potassium carbonate,etc.) may be added thereto. The reaction temperature is 0° C. to 50° C.,preferably 20° C. to 35° C. The reaction time is 3 hr to 7 hr,preferably 5 hr. The molar ratio of compound [V] and compound [IV] or asalt thereof is 1:1 to 1:1.2, preferably 1:1.1. The amount of thecondensing agent is 1.1 equivalent to 1.3 equivalent, preferably 1.2equivalent, relative to compound [V]. The amount of the reactionaccelerator is 0.1 equivalent to 1.0 equivalent, preferably 0.2equivalent, relative to compound [V]. When a base is used, the amountthereof is preferably 1 equivalent relative to the salt of compound[IV].

Step 8

N-[2-(6,6-Dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide(compound [I]) can be obtained by reacting compound [III] in thepresence of an inorganic acid (hydrogen chloride, hydrogen bromide,etc.), in an ether solvent (cyclopentyl methyl ether, tetrahydrofuran,dimethyl ether, diethyl ether, etc.) or in a mixed solvent of an estersolvent (ethyl acetate, etc.) and an alcohol (methanol, ethanol,1-propanol, 2-propanol, etc.), or in an alcohol (methanol, ethanol,1-propanol, 2-propanol, etc.) alone. The reaction temperature is 40° C.to 70° C., preferably 50° C. to 60° C. The reaction time is 30 min to 4hr, preferably 3.5 hr. The amount of the inorganic acid is 2 to 4equivalent, preferably 3 equivalent, relative to compound [III]. Thesolvent for extraction on neutralization with aqueous sodium hydroxidesolution and on washing is preferably cyclopentyl methyl ether.

Step 9

N-[2-(6,6-Dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamidemonohydrochloride (compound [II]) can be obtained by reacting compound[I] with hydrogen chloride in an alcohol (methanol, ethanol, 1-propanol,2-propanol, etc.), an ester solvent (ethyl acetate, etc.) or a mixedsolvent thereof. The amount of the hydrogen chloride is 0.9 equivalentto 1.2 equivalent, preferably 1.05 equivalent, relative to compound [I].The reaction temperature is 40° C. to 70° C., preferably 50° C. to 60°C. The reaction time is 30 min to 2 hr, preferably 1.5 hr. Compound [II]can be precipitated as a crystal by lowering the reaction temperature to0° C. to 30° C.

The purification of compound [II] is performed using an alcohol(ethanol, 1-propanol, 2-propanol, etc.) alone, a mixed solvent of analcohol (ethanol, 1-propanol, 2-propanol, etc.) and an ether solvent(cyclopentyl methyl ether, tetrahydrofuran, etc.), or a mixed solvent ofan alcohol (ethanol, 1-propanol, 2-propanol, etc.) and an ester solvent(ethyl acetate, etc.), preferably 1-propanol.

The purified compound [II] can be obtained by suspending the obtainedcrystals of compound [II] in a solvent, and then by continuouslystirring at the temperature of 90° C. to 100° C. for 6 hr or more,subsequently at 0° C. to 30° C. for 1 hr or more.

Specific features of the production method of the present invention areas follows.

(A) Compound [V] can be obtained from compound [VI] by the progress ofthe following five reactions due one reduction reaction:(1) removal of benzyloxycarbonyl bonding to amino at the 4-position onthe phenyl,(2) reduction of nitro at the 2-position on the phenyl,(3) removal of benzyl from the benzyl 3-oxopropanoate moiety,(4) formation of the indole ring by condensation and cyclizationreaction of the amino formed by the reduction in (2) and the oxo groupof the 3-oxopropanoic acid moiety formed in (3), and(5) decarboxylation reaction after the formation of the indole ring.(B) It is important that the 1-position on the4,5,6,7-tetrahydro-1H-indazole moiety is protected for the followingreasons (1) and (2).(1) When compound [VIII] is used instead of compound [VII] in thereaction of the above-mentioned Step 5, compound [XI] is introduced intonot only the 2-position on the benzyl 3-oxopropanoate moiety, but alsothe 1-position on the 4,5,6,7-tetrahydro-1H-indazole moiety.(2) In the reaction of the above-mentioned Step 7, compound [IV] isintroduced into not only the methylamino at the 6-position on theindole, but also the 1-position on the 4,5,6,7-tetrahydro-1H-indazolemoiety. In fact, in Step 2 of Example 4 in WO 2011/065402,N-{2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl}-N-methylamineis reacted with an amount of 4.6 equivalent of(S)-2-(morpholin-4-yl)propionic acid, together with addition of a base.

As is clear from the below-mentioned Examples, by protecting the1-position on the 4,5,6,7-tetrahydro-1H-indazole moiety, the amount ofcompound [IV] can be reduced to 1 to 1.2 equivalent, preferably 1.1equivalent, relative to compound [V].

(C) The tetrahydropyranyl protecting the 1-position on the4,5,6,7-tetrahydro-1H-indazole moiety serves as a protecting groupwithout being removed in the following steps (1) to (3):(1) the reaction under a basic condition for the production of compound[VI] by reacting compound [VII] with compound [XI],(2) the reduction reaction for the production of compound [V] fromcompound [VI], and(3) the amide bond-forming reaction for the production of compound [III]by reacting compound [V] with compound [IV].(D) The protecting groups exemplified in the following (1) or (2), whichmay be considered as a protecting group of the 1-position on the4,5,6,7-tetrahydro-1H-indazole moiety, cannot be used for the reasonsdescribed therein.(1) When tert-butoxycarbonyl is used, the tert-butoxycarbonyl is removedunder a basic condition in the above-mentioned Step 5.(2) When trimethylsilylethoxymethyl is used, the by-product derived fromtrimethylsilylethoxymethyl after deprotection in the above-mentionedStep 8 can hardly be removed.(E) The tetrahydropyranyl in compound [III] is removed under a mildacidic condition during the conversion into compound [I], and theby-product derived from tetrahydropyranyl can be easily removed.(F) Compound [V] having tetrahydropyranyl at the 1-position on the4,5,6,7-tetrahydro-1H-indazole moiety can be obtained as a crystal.Compound [V] can be obtained with a high purity by crystallization,since the color substance produced in the reaction can be removed, andthe like. Therefore, compound [III], compound [I] and compound [II] canbe obtained with a high purity in a high-yield in the next step orlater.(G) The intermediates industrially produced during the manufacture ofmedicinal chemicals are required to be safe for operation. Whilecompound [XI] and compound [VI] have nitro respectively, the lowpossibility of runaway reaction, the low self-decomposition risk, andthe like were deduced from the results of drop-hammer sensitivitymeasurement, friction sensitivity measurement, differential scanningcalorimetry (DSC) measurement and accelerating rate calorimeter (ARC)measurement.

As described in the above-mentioned (A) to (G), compound [XI], compound[VIII], compound [VII], compound [VI], compound [V] and compound [III]used for the production method of the present invention are usefulcompounds in order to obtain compound [I].

EXAMPLES

The present invention is explained in more detail in the following byreferring to Examples, which are not to be construed as limitative.

Example 1 Synthesis of benzyl (4-fluoro-3-nitrophenyl)carbamate

Under nitrogen atmosphere, sodium hydrogencarbonate (13.9 g, 166 mmol)was dissolved in water (200 mL), and ethyl acetate (150 mL) and4-fluoro-3-nitroaniline (20.0 g, 128 mmol) were added thereto. Benzylchloroformate (24.1 g, 141 mmol) was added dropwise thereto at theinternal temperature of 30° C. or lower. The used container was washedwith ethyl acetate (10 mL), and the washings were also added dropwisethereto. After the completion of the addition, the mixture was stirredat room temperature for 3 hr, left to stand for a while, and separated.The obtained organic layer was filtered, and the filtrate was washedtwice with 5 w/w % brine (100 mL), and concentrated under reducedpressure until the volume became about 80 mL. To this concentratedresidue was added heptane (60 mL) at the internal temperature of 30° C.to 40° C., and the mixture was stirred at the same temperature for 30min. Additional heptane (260 mL) was added thereto, and the mixture wasstirred at room temperature for 2 hr. The precipitated crystals werecollected by filtration, and the obtained wet crystals were washed witha mixed solution of ethyl acetate (6 mL) and heptane (54 mL). The wetcrystals were dried under reduced pressure at the external temperatureof 50° C. to give benzyl 4-fluoro-3-nitrophenylcarbamate (34.6 g, yield93.0%).

¹H-NMR (400 Mz, DMSO-d₆, δ): 10.26 (brs, 1H(NH)), 8.32 (dd, J=6.7, 2.5Hz, 1H), 7.74 (ddd, J=9.1, 3.9, 2.8 Hz, 1H), 7.52 (dd, J=11.1, 9.0 Hz,1H), 7.45-7.31 (m, 5H), 5.17 (s, 2H)

Example 2 Synthesis of benzylN-(4-fluoro-3-nitrophenyl)-N-methylcarbamate

Under nitrogen atmosphere, benzyl 4-fluoro-3-nitrophenylcarbamate (20.0g, 68.9 mmol) was dissolved in N,N-dimethylformamide (120 mL), andcesium carbonate (26.9 g, 82.7 mmol) was added thereto. Methyl iodide(11.7 g, 82.7 mmol) was added dropwise thereto at the internaltemperature of 25° C. or lower, and the mixture was stirred at theinternal temperature of 20° C. to 30° C. for 3 hr. After the completionof the reaction, toluene (200 mL) was added thereto, and water (100 mL)was added thereto at the internal temperature of 35° C. or lower. Thissolution was stirred for about 10 min, left to stand for a while, andseparated. The obtained organic layer was washed twice with water (100mL), and concentrated under reduced pressure until the volume becameabout 100 mL. To this concentrated residue was added heptane (100 mL) atthe internal temperature of 30° C. to 40° C., and the mixture wasstirred at the same temperature for 30 min. Additional heptane (140 mL)was added thereto, and the mixture was stirred at room temperature for 1hr. The precipitated crystals were collected by filtration, and theobtained wet crystals were washed with a mixed solution of toluene (6mL) and heptane (54 mL). The wet crystals were dried under reducedpressure at the external temperature of 50° C. to give benzylN-(4-fluoro-3-nitrophenyl)-N-methylcarbamate (19.3 g, yield 91.9%).

¹H-NMR (400 Mz, DMSO-d₆, δ): 8.17 (dd, J=6.7, 2.8 Hz, 1H), 7.81 (ddd,J=9.0, 3.9, 2.8 Hz, 1H), 7.59 (dd, J=11.3, 9.0 Hz, 1H), 7.38-7.27 (m,5H), 5.13 (s, 2H), 3.28 (s, 3H)

friction sensitivity: JIS grade 7drop-hammer sensitivity: JIS grade 8

Differential scanning calorimetry (DSC) measurement of benzylN-(4-fluoro-3-nitrophenyl)-N-methylcarbamate Decomposition exothermiconset temperature: 272.5° C. decomposition calorimetry: 1.33 kJ/g

measurement conditions

sample: 1.470 mg

container: SUS pressure tight sealed cell

rate of temperature increase: 10° C./min

Example 3 Synthesis of benzyl3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-oxopropanoate

Step 1: Under nitrogen atmosphere,6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazole-3-carboxylic acid (10.0 g,51.5 mmol) and 1,1′-carbonyldiimidazole (9.19 g, 56.7 mmol) weresuspended in tetrahydrofuran (60 mL), to the suspension was addeddropwise N,N-dimethylformamide (20 mL), and the mixture was stirred atthe internal temperature of 20° C. to 30° C. for 1 hr (solution (1)).Step 2: Under nitrogen atmosphere, magnesium chloride (19.6 g, 206 mmol)and monobenzyl potassium malonate (23.9 g, 103 mmol) were suspended intetrahydrofuran (80 mL) in another reaction container, and to thesuspension was added dropwise N,N-dimethylformamide (80 mL) at theinternal temperature of 20° C. to 50° C. The mixture was stirred at theinternal temperature of 60° C. for 30 min, the solution (1) was addedthereto, and the mixture was stirred at the internal temperature of 60to 65° C. for 3 hr. After the completion of the reaction, toluene (100mL) was added thereto, and 10% citric acid solution (100 mL) was addedthereto at the internal temperature of 35° C. or lower. This solutionwas stirred for about 10 min, and separated, and the obtained organiclayer was washed successively with 10% citric acid solution (100 mL), 5%aqueous sodium bicarbonate (100 mL) and water (50 mL×2). The organiclayer was concentrated under reduced pressure until the volume becameabout 20 mL, heptane (40 mL) was added thereto, and the mixture wasstirred at the internal temperature of 50° C. to 60° C. for 30 min.Heptane (40 mL) was added dropwise thereto at the internal temperatureof 45° C. to 55° C., and the mixture was stirred at the same temperaturefor 30 min, and then at room temperature for 2 hr. The precipitatedcrystals were collected by filtration, and the obtained wet crystalswere washed with a mixed solution of toluene (5 mL) and heptane (45 mL).The wet crystals were dried under reduced pressure at the externaltemperature of 40° C. to give benzyl3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-oxopropanoate(14.1 g, yield 83.6%).

¹H-NMR (400 Mz, DMSO-d₆, δ): 13.07 (brs, 1H(NH)), 7.37-7.27 (m, 5H),5.11 (s, 2H), 4.02 (s, 2H), 2.60 (t, J=6.1 Hz, 2H), 2.37 (s, 2H), 1.44(t, J=6.4 Hz, 2H), 0.93 (s, 6H)

Example 4-1 Synthesis of benzyl3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate

Under nitrogen atmosphere, benzyl3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-oxopropanoate(10.0 g, 30.6 mmol) was dissolved in ethyl acetate (80 mL), to thissolution were successively added p-toluenesulfonic acid (0.29 g, 1.53mmol) and 3,4-dihydro-2H-pyran (3.86 g, 45.9 mmol), and the mixture wasstirred at the internal temperature of 15° C. to 25° C. for 4 hr. Afterthe completion of the reaction, 5 w/w % aqueous sodium hydrogencarbonatesolution (40 mL) was added thereto, and the mixture was stirred for 10min, left to stand for a while, and separated. The obtained organiclayer was washed with 10 w/w % brine (40 mL), dried over magnesiumsulfate, and filtered. The organic layer was concentrated under reducedpressure, and the concentrated residue was dissolved in a mixed solutionof hexane and ethyl acetate (4:1), and purified by silica gelchromatography to give benzyl3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate(12 g, yield 95.2%).

The obtained compound in this step is deduced to be a mixture of R-formand S-form, but its ratio is not measured.

¹H-NMR (400 Mz, DMSO-d₆, δ): 7.37-7.27 (m, 5H), 5.40 (dd, J=9.4, 2.7 Hz,1H), 5.11 (s, 2H), 4.01 (dd, J=25.7, 15.7 Hz, 2H), 3.83 (d, J=11.1 Hz,1H), 3.61 (ddd, J=12.4, 8.0, 3.3 Hz, 1H), 2.60 (dt, J=22.3, 8.7 Hz, 2H),2.45 (dd, J=47.3, 17.0 Hz, 2H), 2.16 (tt, J=15.0, 5.3 Hz, 1H), 2.00-1.90(m, 1H), 1.85-1.77 (m, 1H), 1.70-1.55 (m, 1H), 1.55-1.45 (m, 2H), 1.44(t, J=6.4 Hz, 2H), 0.94 (d, J=12.3 Hz, 6H)

Example 4-2 Synthesis of benzyl3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate

Under nitrogen atmosphere, benzyl3-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-3-oxopropanoate(20.0 g, 61.3 mmol) was dissolved in ethyl acetate (150 mL), and to thissolution were successively added p-toluenesulfonic acid (1.17 g, 6.13mmol) and dihydropyran (7.73 g, 92.0 mmol). The used container waswashed with ethyl acetate (10 mL), and the washings were also addedthereto. The mixture was stirred at the internal temperature of 15° C.to 30° C. for 2.5 hr, 5 w/w % aqueous sodium hydrogencarbonate solution(40 mL) was added thereto, and the mixture was stirred for a while, andseparated. The obtained organic layer was washed with 10 w/w % brine (80mL), and concentrated under reduced pressure until the volume becameabout 60 mL. To the concentrated residue was added ethyl acetate (100mL), and the mixture was again concentrated under reduced pressure untilthe volume became about 60 mL. To the concentrated residue was addedethyl acetate (100 mL), and the mixture was again concentrated underreduced pressure until the volume became about 60 mL. To thisconcentrated residue was added N,N-dimethylacetamide (60 mL), and themixture was again concentrated under reduced pressure until the volumebecame about 80 mL to give a solution of benzyl3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate.

The obtained compound in this step is deduced to be a mixture of R-formand S-form, but its ratio is not measured.

Example 5-1 Synthesis of benzyl2-[4-(N-benzyloxycarbonyl-N-methylamino)-2-nitrophenyl]-3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate

Under nitrogen atmosphere, to a solution of benzyl3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate(142 mg, 0.346 mmol) in dimethyl sulfoxide (0.71 mL) were successivelyadded benzyl N-(4-fluoro-3-nitrophenyl)-N-methylcarbamate (100 mg, 0.329mmol) and potassium carbonate (96 mg, 0.692 mmol), and the mixture wasstirred in an oil bath of 90° C. for 2 hr and 20 min. After thecompletion of the reaction, the reaction solution was cooled to roomtemperature, and poured into 5 w/w % aqueous citric acid solution. Then,the mixture was extracted with ethyl acetate, and separated, and theobtained organic layer was washed successively with water and saturatedbrine. The obtained organic layer was dried over anhydrous sodiumsulfate, the anhydrous sodium sulfate was removed by filtration, and thefiltrate was concentrated under reduced pressure. The residue waspurified by column chromatography (hexane:ethyl acetate 3:1 to 2:1) togive benzyl2-[4-(N-benzyloxycarbonyl-N-methylamino)-2-nitrophenyl]-3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate(184 mg, yield 81%).

The obtained compound in this step is deduced to be a mixture ofdiastereomers and/or tautomers, but its ratio is not measured.

¹H-NMR (DMSO-D₆, δ): 8.11 (dd, J=13.9, 2.4 Hz, 1H), 7.74 (td, J=8.2, 2.4Hz, 1H), 7.45 (dd, J=8.5, 3.0 Hz, 1H), 7.39-7.23 (m, 10H), 6.32 (d,J=9.0 Hz, 1H), 5.43-5.34 (m, 1H), 5.26-5.18 (m, 2H), 5.16 (d, J=4.4 Hz,2H), 3.81-3.68 (m, 1H), 3.64-3.52 (m, 1H), 3.31 (d, J=5.3 Hz, 3H),2.65-2.56 (m, 2H), 2.55-2.30 (m, 2H), 2.12-2.00 (m, 1H), 1.97-1.82 (m,1H), 1.77-1.67 (m, 1H), 1.67-1.35 (m, 5H), 0.94 (dd, J=11.9, 6.0 Hz, 6H)

Differential Scanning Calorimetry (DSC) Measurement of Benzyl2-[4-(N-benzyloxycarbonyl-N-methylamino)-2-nitrophenyl]-3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate

Decomposition exothermic onset temperature: 120.8° C.decomposition calorimetry: 848.3 J/gmeasurement conditions

sample: 3.390 mg

container: SUS pressure tight sealed cell

rate of temperature increase: 10° C./min

Example 5-2 Synthesis of benzyl2-[4-(N-benzyloxycarbonyl-N-methylamino)-2-nitrophenyl]-3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate

Under nitrogen atmosphere, to a solution of benzyl3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate,which was obtained in Example 4-2, were successively added benzylN-(4-fluoro-3-nitrophenyl)-N-methylcarbamate (18.6 g, 61.3 mmol) andtripotassium phosphate (32.5 g, 153 mmol), the used container was washedwith N,N-dimethylacetamide (20 mL), and the washings were also addedthereto. The mixture was stirred at the internal temperature of 50° C.to 60° C. for 23 hr, and then at the internal temperature of 70° C. to80° C. for 5.5 hr. After the completion of the reaction, toluene (100mL) was added thereto at the internal temperature of 40° C. or lower,and water (160 mL) was added thereto at the internal temperature of 30°C. or lower. This solution was stirred at room temperature for about 30min, and separated, and the obtained organic layer was washedsuccessively with 10 w/w % aqueous citric acid solution (80 mL), 5 w/w %aqueous sodium hydrogencarbonate solution (80 mL) and 10 w/w % brine (80mL). The obtained organic layer was concentrated under reduced pressureuntil the volume became about 80 mL to give a solution of benzyl2-[4-(N-benzyloxycarbonyl-N-methylamino)-2-nitrophenyl]-3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate.

The obtained compound in this step is deduced to be a mixture ofdiastereomers and/or tautomers, but its ratio is not measured.

Example 6 Synthesis ofN-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine

A solution of benzyl2-[4-(N-benzyloxycarbonyl-N-methylamino)-2-nitrophenyl]-3-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-3-oxopropanoate,which was obtained in Example 5-2, was charged into a pressure tightbottle, the used container was washed with toluene (20 mL), and thewashings were also added thereto. Then, methanol (120 mL) and 5 w/w %palladium on carbon (PE type, 50% wet, 4.0 g) were added thereto, thereaction system was purged with hydrogen, and the mixture was stirredunder hydrogen pressure of 3 atm to 4 atm for 24 hr. After thecompletion of the reaction, tetrahydrofuran (140 mL) was added thereto,and the precipitated crystals were dissolved. The palladium on carbonwas removed by filtration, and washed with tetrahydrofuran (20 mL). Theobtained filtrate and the washings were combined, and concentrated underreduced pressure until the volume became about 60 mL. To theconcentrated residue was added toluene (100 mL), and the mixture wasagain concentrated under reduced pressure until the volume became about60 mL. To the concentrated residue was added toluene (100 mL), and themixture was again concentrated under reduced pressure until the volumebecame about 60 mL. To the obtained concentrated residue was added2-propanol (40 mL) at the internal temperature of 45° C. to 55° C., andthe mixture was stirred at the same temperature for 1 hr, and then atroom temperature for 1 hr. The precipitated crystals were collected byfiltration, and the obtained wet crystals were washed with a mixedsolution of toluene (8 mL) and 2-propanol (32 mL). The wet crystals weredried under reduced pressure at the external temperature of 50° C. togiveN-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine(18.5 g, yield 79.8%, LC purity 99.3%).

The obtained compound in this step is deduced to be a mixture of R-formand S-form, but its ratio is not measured.

¹H-NMR (400 Mz, DMSO-d₆, δ): 10.60 (d, J=1.4 Hz, 1H), 7.19 (d, J=8.5 Hz,1H), 6.50 (d, J=1.9 Hz, 1H), 6.40-6.35 (m, 2H), 5.36-5.29 (m, 2H), 3.92(d, J=11.8 Hz, 1H), 3.58-3.66 (m, 1H), 2.68 (d, J=5.1 Hz, 3H), 2.60 (t,J=6.0 Hz, 2H), 2.34-2.45 (m, 2H), 2.08-1.99 (m, 1H), 1.86 (dd, J=13.0,2.7 Hz, 1H), 1.75-1.62 (m, 1H), 1.55 (t, J=6.2 Hz, 4H), 1.01 (d, J=10.9Hz, 6H)

LC Analysis Condition forN-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine

column: YMC-triart C18 5 μm 4.6×150 mm

column temperature: constant temperature around 40° C.

mobile phase A: 10 mmol/L phosphate buffer solution

mobile phase B: MeCN

gradient condition:

TABLE 1 Time (min) 0 2 10 19 20 25 mobile phase A (%) 90 90 10 10 90 90mobile phase B (%) 10 10 90 90 10 10

flow rate: 1.5 mL/min

detection method: UV 254 nm

injected amount: 10 μL

analysis time: 20 min

retention time: about 10.0 min

preparation method of mobile phase A: NaH₂PO₄.2H₂O (2.34 g) is dissolvedin water (3 L), and 85% H₃PO₄ (1.0 mL) is added thereto. This solutionis filtered through a filter (0.45 μm), and the filtrate is degassedwell, and then used for LC analysis.

Powder X-ray Diffraction Measurement ofN-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine

The sample was fixed on an aluminium cell, and powder X-ray diffractionwas measured using powder X-ray diffraction apparatus (PANalytical X′pert Pro) under the condition of X-ray source: Cu, tube voltage: 45 kV,tube current: 40 mA, scan speed: 0.418°/sec, step width: 0.0334° anddiffraction angle: 3° to 25° to give a diffraction pattern. The obtaineddiffraction pattern is shown in FIG. 1.

diffraction peak: 2θ=9.59, 10.6, 11.0, 11.7, 14.0, 14.4, 14.8, 15.1,16.7, 17.9, 18.7, 18.9, 19.2, 19.8, 20.1, 20.4, 20.6, 20.9, 21.6, 21.9,23.3, 23.9, 24.2, 24.5°.

Example 7-1N-[2-(6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide

Under nitrogen atmosphere,N-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine(1.50 g, 3.96 mmol) was dissolved in N,N-dimethylformamide (7.5 mL), and(S)-2-(morpholin-4-yl)propanoic acid (694 mg, 4.36 mmol),1-hydroxybenzotriazole monohydrate (606 mg, 3.96 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (836 mg,4.36 mmol) were successively added thereto at room temperature, and themixture was stirred at room temperature for 5 hr. After the completionof the reaction, the reaction solution was poured into aqueous sodiumhydrogencarbonate solution, and the mixture was stirred at the sametemperature for 30 min. The precipitated solid was collected byfiltration, and washed successively with aqueous sodiumhydrogencarbonate solution and water. The obtained wet crystals weredried to giveN-[2-(6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide(1.92 g, yield 93%).

The obtained compound in this step is deduced to be a mixture of SR-formand SS-form, but its ratio is not measured.

¹H-NMR (DMSO-D₆, δ): 11.31 (s, 1H), 7.54 (d, J=8.1 Hz, 1H), 7.31 (s,1H), 6.89 (d, J=8.1 Hz, 1H), 6.63 (s, 1H), 5.34 (d, J=9.7 Hz, 1H),3.97-3.87 (m, 1H), 3.69-3.56 (m, 1H), 3.52-3.43 (m, 4H), 3.20-3.15 (m,4H), 2.69-2.60 (m, 2H), 2.57-2.33 (m, 5H), 2.30-2.18 (m, 2H), 2.07-1.96(m, 1H), 1.92-1.82 (m, 1H), 1.75-1.61 (m, 1H), 1.61-1.46 (m, 4H),1.05-0.94 (m, 3H), 1.01 (d, J=9.0 Hz, 6H)

Example 7-2N-[2-(6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide

Under nitrogen atmosphere,N-[2-[6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl]-1H-indol-6-yl]-N-methylamine(10.0 g, 26.4 mmol) was dissolved in N,N-dimethylformamide (50 mL), and(S)-2-(morpholin-4-yl)propanoic acid monohydrochloride (5.67 g, 29.0mmol), sodium hydrogencarbonate (2.44 g, 29.0 mmol),1-hydroxybenzotriazole monohydrate (0.81 g, 5.28 mmol) and1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (6.08 g,31.7 mmol) were successively added thereto at room temperature, and themixture was stirred at the internal temperature of 20° C. to 35° C. for5 hr. After the completion of the reaction, cyclopentyl methyl ether(100 mL) and 10 w/w % brine (50 mL) were added thereto at the internaltemperature of 0° C. to 30° C., and the mixture was stirred at the sametemperature for 30 min. The mixture was left to stand for a while, andseparated, and the obtained organic layer was concentrated under reducedpressure until the volume became about 30 mL. To the concentratedresidue was added cyclopentyl methyl ether (70 mL), and the mixture wasagain concentrated under reduced pressure until the volume became about30 mL. To the concentrated residue was added cyclopentyl methyl ether(70 mL), and the mixture was again concentrated under reduced pressureuntil the volume became about 30 mL. The volume was adjusted to about 60mL by addition of cyclopentyl methyl ether to give a solution ofN-[2-(6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide.

The obtained compound in this step is deduced to be a mixture of SR-formand SS-form, but its ratio is not measured.

Example 8-1 Synthesis ofN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide

Under nitrogen atmosphere,N-[2-(6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide(1.88 g, 3.62 mmol) was dissolved in methanol (18.8 mL), and 2Nhydrochloric acid (5.43 mL) was added thereto. The mixture was stirredfor 2 hr and 10 min in an oil bath of 60° C. After the completion of thereaction, the mixture was cooled to room temperature, and concentratedunder reduced pressure. To the residue were added ethyl acetate andwater, and the mixture was extracted and separated. To the obtainedaqueous layer was added ethyl acetate, and the pH of the mixture wasadjusted to 8 with sodium hydrogencarbonate while stirring at roomtemperature. After extraction and separation, and the obtained organiclayer was washed with saturated brine, and dried over anhydrous sodiumsulfate. The anhydrous sodium sulfate was removed by filtration, and thefiltrate was concentrated under reduced pressure to giveN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide(1.52 g, yield 96%).

¹H-NMR (DMSO-D₆, δ): 12.53 (s, 1H), 11.40 (s, 1H), 7.53 (d, J=8.1 Hz,1H), 7.27 (s, 1H), 6.87 (d, J=8.6 Hz, 1H), 6.58 (s, 1H), 3.50-3.44 (m,4H), 3.21-3.15 (m, 1H), 3.17 (s, 3H), 2.65 (t, J=6.0 Hz, 2H), 2.47-2.36(m, 4H), 2.30-2.18 (m, 2H), 1.56 (t, J=6.3 Hz, 2H), 1.00 (d, J=16.2 Hz,3H), 0.99 (s, 6H)

Example 8-2 Synthesis ofN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide

Under nitrogen atmosphere, to a solution ofN-[2-(6,6-dimethyl-1-(tetrahydropyran-2-yl)-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide,which was obtained in Example 7-2, was added dropwise 2N hydrogenchloride-ethanol solution (39.6 mL) at the internal temperature of 15°C. to 60° C., and the mixture was stirred at the internal temperature of50° C. to 60° C. for 3.5 hr. After the completion of the reaction, thissolution was added dropwise to a mixed solution of 1N aqueous sodiumhydroxide solution (84.5 mL) and cyclopentyl methyl ether (350 mL) atthe internal temperature of 0° C. to 60° C., the used container waswashed with ethanol (20 mL), and the washings were also added thereto.After confirming that the pH of the aqueous layer was 9 or more, themixture was separated at the internal temperature of 40° C. to 50° C.,and the obtained organic layer was washed three times with water (100mL) at the same temperature, and concentrated under reduced pressureuntil the volume became about 30 mL. To the concentrated residue wasadded ethyl acetate (70 mL), and the mixture was again concentratedunder reduced pressure until the volume became about 30 mL. To theconcentrated residue was added ethyl acetate (70 mL), and the mixturewas again concentrated under reduced pressure until the volume becameabout 30 mL to give a solution ofN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide.

Example 9 Synthesis ofN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamidemonohydrochloride

Step 1

To a solution ofN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamide,which was obtained in Example 8-2, was added 1-propanol (15 mL), and theinsoluble substance was removed by filtration. The used container andfilter were washed with 1-propanol (15 mL). The filtrate and washingswere combined, and 4N hydrogen chloride-ethyl acetate solution (2.64 mL,10.6 mmol) was added dropwise thereto at the internal temperature of 50°C. to 60° C. The mixture was stirred at the same temperature for 1 hr,and 4N hydrogen chloride-ethyl acetate solution (3.96 mL, 15.8 mmol) wasadded dropwise thereto. The mixture was stirred at the same temperaturefor 30 min, ethyl acetate (90 mL) was added dropwise thereto, and themixture was stirred for 1 hr. The mixture was stirred overnight at roomtemperature, and the precipitated crystals were collected by filtration.The obtained wet crystals were washed with a mixed solution of1-propanol (4 mL) and ethyl acetate (16 mL), and then ethyl acetate (20mL). The wet crystals were dried under reduced pressure at the externaltemperature of 50° C. to giveN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamidemonohydrochloride (11.0 g, yield 88.0%).

Step 2

Under nitrogen atmosphere,N-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamidemonohydrochloride (4.0 g) was suspended in 1-propanol (18 mL), and thesuspension was stirred at the internal temperature of 90° C. to 100° C.for 7.5 hr, and then overnight at room temperature. The crystals werecollected by filtration, and the obtained wet crystals were washed with1-propanol (8 mL). The wet crystals were dried under reduced pressure atthe external temperature of 65° C. to giveN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamidemonohydrochloride (3.48 g, yield 87.0%, LC purity 99.9% or more).

¹H-NMR (400 Mz, DMSO-d₆, δ): 11.54 (s, 1H), 10.35 (brs, 1H), 7.62 (d,J=8.3 Hz, 1H), 7.38 (s, 1H), 6.98 (dd, J=8.3, 1.8 Hz, 1H), 6.65 (s, 1H),4.95-3.75 (m, 4H), 3.70 (t, J=12.1 Hz, 1H), 3.47-2.96 (m, 7H), 2.66 (t,J=6.1 Hz, 2H), 2.42 (s, 2H), 1.56 (t, J=6.4 Hz, 2H), 1.35 (d, J=6.5 Hz,3H), 1.01 (s, 6H)

LC analysis condition forN-[2-(6,6-dimethyl-4,5,6,7-tetrahydro-1H-indazol-3-yl)-1H-indol-6-yl]-N-methyl-(2S)-2-(morpholin-4-yl)propanamidemonohydrochloride

column: YMC-triart C18 5 μm 4.6×150 mm

column temperature: constant temperature around 40° C.

mobile phase A: 20 mmol/L phosphate buffer solution

mobile phase B: MeCN

gradient condition:

TABLE 2 Time (min) 0 2 10 25 30 mobile phase A (%) 80 80 40 40 80 mobilephase B (%) 20 20 60 60 20

flow rate: 1.5 mL/min

detection method: UV 220 nm

injected amount: 10 μL

analysis time: 30 min

retention time: about 12.7 min

preparation method of mobile phase A: KH₂PO₄ (4.08 g) and K₂HPO₄ (5.23g) are exactly weighed, and dissolved in water (3 L). This solution arefiltered through a filter (0.45 μm), and the filtrate is degassed well,and then used for LC analysis.

INDUSTRIAL APPLICABILITY

The compound of the present invention is useful as a syntheticintermediate for producing a compound of the formula [II].

The present invention can provide a method for producing a compound ofthe formula [II] in good yield.

The production method of the present invention can be performed in a fewsteps without a reagent that needs careful handling due to danger andtoxicity, and therefore it is useful as an industrial large-scalesynthetic method.

1. A method of producing a compound of the formula [I]

which comprises a step of removing the protecting group from a compoundof the formula [III]

to give a compound of the formula [I].
 2. A method of producing acompound of the formula [II]

which comprises a step of treating a compound of the formula [I]

with hydrogen chloride to give a compound of the formula [II].
 3. Amethod of producing a compound of the formula [II]

which comprises a step of removing the protecting group from a compoundof the formula [III]

to give a compound of the formula [I], and a step of treating a compoundof the formula [I]

with hydrogen chloride to give a compound of the formula [II].
 4. Themethod of claim 1 or 3, which further comprises a step of reacting acompound of the formula [V]

with a compound of the formula [IV]

or a reactive derivative thereof or a salt thereof to give a compound ofthe formula [III]


5. The method of claim 4, which further comprises a step of subjecting acompound of the formula [VI]

wherein R¹ and R² are each independently hydrogen, C₁₋₆ alkyl or C₁₋₆alkoxy, to a reduction reaction to give a compound of the formula [V]


6. The method of claim 5, which further comprises a step of reacting acompound of the formula [VII]

with a compound of the formula [XI]

to give a compound of the formula [VI]


7. The method of claim 6, which further comprises a step of subjecting acompound of the formula [VIII]

to tetrahydropyranylation to give a compound of the formula [VII]


8. The method of claim 7, which further comprises a step of reacting acompound of the formula [IX]

with a compound of the formula [X]

wherein M is sodium or potassium, to give a compound of the formula[VIII]


9. The method of claim 2 or 3, which further comprises a step ofpurifying a compound of the formula [II]

with 1-propanol.
 10. (canceled)
 11. A compound of the formula [V]


12. A compound of the formula [III]


13. A compound of the formula [VI]

wherein R¹ and R² are each independently hydrogen, C₁₋₆ alkyl or C₁₋₆alkoxy.
 14. A compound of the formula [VII]

wherein R¹ is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkoxy.
 15. A compound of theformula [VIII]

wherein R¹ is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkoxy.
 16. A compound of theformula [XI]

wherein R² is hydrogen, C₁₋₆ alkyl or C₁₋₆ alkoxy.